This application is to establish a U54 Medication Development Center of Excellence (MDCE). The proposed MDCE will be integrated within the umbrella of the Penn/VA Center for Studies of Addiction (CSA) and benefits greatly from that integration, permitting access to infrastructure and resources not generally available outside of a large research center. The MDCE has priority access to important resources: 1) the Berrettini genetics lab 2) the Center biostatistician; 3) a web-based Data Management Unit; and, 4) state-of the-art Brain Imaging. Our theme is the identification and comprehensive screening of innovative medications for the treatment of Cocaine Use Disorder (CUD). Our MDCE proposes to emphasize novel medications such as BP1.4979, a dopamine D3 partial agonist, the GABA B agonist, long acting baclofen and clavulanic acid (CLAV). In addition, we will improve our ability to identify efficacious new medications by identifying characteristics of CUD patients that may increase their likelihood of responding positively to a particular medication and by streamlining the identification of medication responders in clinical trials. The Administrative Core will coordinate and integrate a Human Laboratory and Genetics Pilot Program, an Education Core, a Biostatistics and Data Management Core and three research projects. The Human Laboratory and Genetics Pilot Program will employ neurobehavioral tasks that may aid in the detection of medication responders early in treatment and will explore pharmacogenetic interactions that could explain and potentially capitalize on heterogeneity in medication response. The research projects are arranged to allow for novel medications to be studied from safety through preliminary efficacy. In Project 1, we will administer cocaine to volunteers while receiving either BPI .4979 or CLAV to test for potential toxic interactions with cocaine, providing safety and preliminary efficacy data for these compounds. Project 2 will provide neurobehavioral and neuroimaging data to determine whether medications selected for study effectively engage the appropriate brain targets at the dosages proposed for study. Project 3 proposes to evaluate promising novel compounds in 12-week, placebo-controlled trials. By providing comprehensive screening of candidate medications and sequentially testing them, as described, we expect to rapidly identify effective medications that justify investment in the next level of development, multi-site efficacy trials.